The major epileptic syndromes with onset in infancy or later in life are characterized by modulation of epileptiform activity in synchrony with sleep-wake cycling. Most commonly epileptiform activity is augmented, at times drastically, during non-rapid eye movement (NREM) sleep. Preliminary results using immature rats with tetanus toxin induced epilepsy reveal similar NREM augmentation of epileptiform activity. The goal of the proposed studies is to improve our understanding of the mechanisms underlying modulation of epileptiform activity during sleep-wake cycling in developing brain. NREM sleep is characterized by increased activity in brainstem monoaminergic (noradrenergic and serotonergic) systems. The noradrenergic brainstem nuclei (Locus ceruleus) have widespread cortical projections making it possible for this system to modulate cortical neuronal activity. There is experimental evidence that beta-adrenergic receptor activation increases epileptiform activity in adult rat hippocampal slices. Studies have shown that this occurs in infant rats as well but is more dramatic. Intracellular neurophysiologic studies in adult hippocampal slice preparations have shown that activation of the beta- adrenergic receptor suppresses the slow after hyperpolarization (sAHP) that normally follows the paroxysmal depolarization shift (PDS). Blockade of this potential shortens the post PDS refractory period and thus it is thought to lead to the increases in interictal spike frequency observed experimentally. The beta-adrenergic receptor is a G-protein linked receptor. Ligand binding to the beta-adrenergic receptor mediates G protein activation of adenylyl cyclase. As a result, intracellular cyclic adenosine monophosphate (cAMP) levels increase. This in turn activates cAMP dependent protein kinase (PKA). Activation of PKA has been shown to phosphorylate a protein closely associated with a slow calcium activated potassium channel in hippocampal neurons. Protein phosphorylation leads to reduction in potassium conductance through this channel and a blockade of the sAHP. Based on these ideas, we hypothesize that beta-adrenergic receptor activation and this second messenger cascade mediate NREM sleep augmentation of epileptiform activity. Through the use of a tetanus toxin induced epilepsy model in immature rats, the proposed experiments will further define sleep modulation of epileptiform activity by manipulating the beta-adrenergic system in vivo. Experiments are also proposed to record intracellular and extracellular changes in epileptiform activity in hippocampal slices from these animals following pharmacological manipulation of the beta-adrenergic system. By further defining the role of beta-adrenergic modulation of epileptiform activity in immature brain, we hope to better understand the basic processes contributing to seizures in early life. Thus, these studies will hopefully lead to new avenues of treatment of the epilepsies of infancy and childhood.